Here we examine the molecular mechanisms regulating synovial tissue architecture and function. The synovial lining demonstrates cellular compaction of fibroblast-like synoviocytes (FLS) and macrophages within an ordered extracellular matrix. In inflammatory arthritis, this lining exhibits marked hyperplasia and pannus formation and functionally acquires the ability to migrate over, attach to, and erode into adjacent cartilage and bone. The major mesenchymal cells of the synovial lining, the FLS, are thought to be intimately involved in regulating the physiology and architecture of the normal synovial membrane and of the abnormal synovium in inflammatory arthritis. We found that the cadherin family of proteins, specifically cadherin-11, is expressed on FLS and is a major factor in their cellular adhesion, migration and invasion and in formation of the synovial lining. Strikingly, in cadherin-11 deficient mice, the synovial lining is hypoplastic at baseline and further, the synovium lacks the typical changes seen in inflammatory arthritis. In cadherin-11 null mice, the inflammatory response in arthritis is attenuated and the synovium does not attach to or invade cartilage. The specific aims of this proposal are focused on elaborating the role of cadherin-11 in the production of matrix and synovlocyte proliferation (Aim 1), the capacity of FLS to migrate, attach to, and erode cartilage (Aim 2) and on their ability to participate in the inflammatory reaction and interact with macrophages in the synovium in in vitro models (Aim 3). Then, we will determine if cadherin-11 might serve as a new therapeutic target for inflammatory arthritis in vivo, reducing both the inflammatory reaction and cartilage damage alone or in combination with anti-TNF therapy (Aim 4). Together, these studies will reveal newly identified mechanisms relevant to understanding synovitis as well as point to potential therapeutic approaches that target FLS in inflammatory arthritis based on the expression and function of cadherin-11.